The neuroprotective impact of the leak potassium channel TASK1 on stroke development in mice.
Oxygen depletion (O(2)) and a decrease in pH are initial pathophysiological events in stroke development, but secondary mechanisms of ischemic cell death are incompletely understood. By patch-clamp recordings of brain slice preparations we show that TASK1 and TASK3 channels are inhibited by pH-reduction (42+/-2%) and O(2) deprivation (36+/-5%) leading to membrane depolarization, increased input resistance and a switch in action potential generation under ischemic conditions. In vivo TASK blockade by anandamide significantly increased infarct volumes at 24 h in mice undergoing 30 min of transient middle cerebral artery occlusion (tMCAO). Moreover, blockade of TASK channels accelerated stroke development. Supporting these findings TASK1(-/-) mice developed significantly larger infarct volumes after tMCAO accompanied by worse outcome in functional neurological tests compared to wild type mice. In conclusion, our data provide evidence for an important role of functional TASK channels in limiting tissue damage during cerebral ischemia.
Meuth
Sven G
SG
University of Würzburg, Department of Neurology, Würzburg, Germany. meuth_s@klink.uni-wuerzburg.de
Kleinschnitz
Christoph
C
Broicher
Tilman
T
Austinat
Madeleine
M
Braeuninger
Stefan
S
Bittner
Stefan
S
Fischer
Stephan
S
Bayliss
Douglas A
DA
Budde
Thomas
T
Stoll
Guido
G
Wiendl
Heinz
H
D000138:Acidosis / Q000503:physiopathology; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology*; D063388:Endocannabinoids; D002534:Hypoxia, Brain / Q000503:physiopathology; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors; D020521:Stroke / Q000503:physiopathology*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors; D013788:Thalamus / Q000473:pathology / Q000503:physiopathology
D001095:Arachidonic Acids; D063388:Endocannabinoids; D009419:Nerve Tissue Proteins; D053284:Polyunsaturated Alkamides; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C511784:TASK3 protein, mouse; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C420132:potassium channel subfamily K member 3; C078814:anandamide